Cutaneous squamous cell carcinoma (SCC), along with basal cell carcinoma (BCC), comprise the non-melanoma skin cancers (NMSC), the most common cancer in Caucasians, with more than 3,000,000 new cases diagnosed annually in the United States. While not usually fatal, SCC may repeatedly recur and result in death in a small proportion of patients, and a history of SCC has been consistently associated with an increased risk of several other types of cancers. Despite the current knowledge about the harms of sun exposure, and increased use of sunscreen, SCC incidence rates continue to increase, emphasizing the public health importance of this highly prevalent cancer, and highlighting the need for an increased understanding of its etiology and control. Accumulating evidence suggests that cutaneous human papillomavirus (HPV) infection may be a risk factor for developing NMSC, particularly SCC. DNA from cutaneous HPV types in multiple genera has been detected in up to 50% of SCC tissues from immuno-competent individuals. In addition, several case-control studies have demonstrated statistically significant associations between SCC and antibodies against cutaneous HPV types, presence of HPV DNA in eyebrow hair follicles or HPV DNA in normal skin samples. Tumor-based HPV DNA detection and serology measurements were incorporated into our own case-control study, in which cutaneous HPV seroreactivity was significantly associated with HPV DNA-positive SCC, with antibodies detected for the same HPV types that were present in the tumor tissue. In the same study, SCC was also associated with another cutaneous virus, Merkel cell polyomavirus (MCV), with MCV DNA-positive cases having significantly higher MCV antibody levels than controls. Although the case-control data are highly compelling, causal associations between cutaneous papillomavirus and polyomavirus infections cannot be established in the absence of prospective data that clearly demonstrate the presence of the viral infections prior to the onset of disease. We propose to conduct a prospective cohort study of individuals at risk for SCC, obtaining multiple biospecimens for the measurement of cutaneous HPV and MCV infections, and following participants for up to four years, conducting full body skin exams for the detection of incident SCC. The goal of the proposed research is to estimate the risk of SCC associated with cutaneous HPV and MCV infections and to demonstrate type-specific concordance between viral infections in normal tissues and subsequent NMSC lesions. The proposed study would provide the critical evidence needed for establishing causality between cutaneous viral infections and SCC.